Clinical analysis of pathologic complete responders in advanced-stage ovarian cancer.

OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.

Pathological factors associated with non-sentinel lymph node metastasis in early stage cervical cancer.

OBJECTIVE: To analyze the predictive factors for non-sentinel lymph node (non-SLN) metastasis in early-stage cervical cancer. METHODS: We analyzed a series of 113 patients who underwent sentinel lymph node (SLN) mapping for cervical cancer. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The overall bilateral detection rate was 81.5%, with a median of two SLNs resected. The study ultimately included 92 patients with SLNs that were mapped who had also undergone systematic pelvic lymph node dissection. Thirteen (14.1%) patients had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, one (1.1%) had isolated tumor cells (ITC), seven (7.6%) had micrometastases, and five (5.4%) had macrometastases. Notably, 46.1% (6/13) had lymph node metastases detected only after IHC. Five (38.5%) cases had positive non-SLNs, with a median count of one positive lymph node. Parametrial invasion was the only risk factor for positive non-SLN (p = .045). Regarding the size of SLN metastasis, non-SLN involvement was present in the only case with ITC (1/1), 42.9% (3/7) of cases with micrometastases, and in 20% (1/5) with macrometastases. CONCLUSIONS: Our data suggest that parametrial invasion correlates with the risk of non-SLN metastasis in cervical cancer.

Genomic profiling in ovarian cancer retreated with platinum based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes.

BACKGROUND: Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity. METHODS: In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS. RESULTS: The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment. CONCLUSIONS: HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.

Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil.

BACKGROUND: BRCA1/2 pathogenic (P) and likely pathogenic (LP) germline variants are frequent among patients with ovarian carcinoma. However, these variants have not been extensively characterized in patients with ovarian cancer in Brazil. METHODS: In this retrospective study we evaluated clinical characteristics and BRCA1/2 genetic test results from patients with ovarian carcinoma who underwent genetic counseling at A.C.Camargo Cancer Center (Brazil) between 2015 and 2017 and had performed germline genetic testing of BRCA1/2 genes. RESULTS: Among 158 patients, 33 P and LP variants and were found (20.8%), 27 in BRCA1 and six in BRCA2, and six variants of unknown clinical significance (VUS). Thirteen percent of the patients did not have Multiplex Ligation-dependent Probe Amplification (MLPA) results. Three P variants in BRCA1 were found in more than one patient: c.5266dupC (p.Gln1756Profs*74), c.3331_3334delCAAG (p.Gln1111Asnfs5*), and c.211A > G (p.Arg71Gly). One LP variant in BRCA1 had not been previously described, c.4153_4154delCT (p.Leu1385Ilefs*5). Patients with previous diagnosis of breast cancer were carriers of P or LP variant in 8 of 12 cases (66.7%), and patients with a family history of ovarian or breast cancer in first- or second-degree relatives were carriers of P or LP variant in 26.7% of cases compared to 16.9% for patients without family history (p = 0.166). CONCLUSION: Prevalence of BRCA1/2 germline P and LP variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.

Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery and the Risk of Platinum Resistance in Epithelial Ovarian Cancer.

BACKGROUND: Interval debulking surgery (IDS) is an option for treating patients with advanced ovarian carcinoma. Two randomized trials have shown similar survival rates for primary debulking surgery (PDS) and IDS. One of the concerns with IDS is the potentially higher risk of inducing platinum resistance when treating patients with greater disease volume. METHODS: A retrospective review of data on 237 patients with stage IIIC and IV ovarian carcinoma who were treated at a single institution from 2000 to 2013. We analyzed the association of IDS with time to first platinum resistant relapse (TTPR); platinum-resistant disease at first relapse, defined as a platinum-free interval (PFI) after first-line chemotherapy of <6 months; and overall response rate (ORR) to chemotherapy at first platinum-sensitive relapse. RESULTS: The TTPR was 60 months, and the median TTPR was longer for the PDS (80.8 months) versus IDS group (39.3 months; p = 0.012) and for patients with residual disease (RD) ≤10 mm (80.8 months) compared with those with RD >10 mm (26.1 months; p < 0.001). In the multivariate analysis, IDS [hazard ratio (HR) 1.92; p = 0.009] and RD >10 mm (HR 1.65; p < 0.001) retained an increased risk of developing platinum-resistant disease. IDS was not associated with a greater risk of PFI <6 months at first relapse, and the ORR to platinum-based chemotherapy at first platinum-sensitive relapse was 87.2 % for patients who were treated with PDS compared with 68.0 % for those who underwent IDS (p = 0.051). CONCLUSIONS: IDS correlates with a higher risk of the development of platinum resistance.

Low PTEN expression is associated with worse overall survival in head and neck squamous cell carcinoma patients treated with chemotherapy and cetuximab.

BACKGROUND: Platinum-based chemotherapy associated with cetuximab is the first-line treatment for inoperable recurrence or metastatic head and neck squamous cell carcinoma (HNSCC). There is no established biomarker for cetuximab efficacy in HNSCC. The PI3K pathway is one of the most frequently altered pathways in HNSCC. Loss of phosphatase and tensin homolog (PTEN) expression occurs in up to 30 % of cases. METHODS: This was a retrospective analysis of data from 61 patients with inoperable recurrence or metastatic HNSCC treated with cetuximab. PTEN, epidermal growth factor receptor and p16 expression were analyzed by immunohistochemistry and tested for association with clinical outcomes. RESULTS: Median overall survival was 11.4 months and progression-free survival was 6.9 months. Low PTEN expression was present in 26.2 % of patients and identified patients with worse prognosis. p16 was positive in only 8.5 % of tumors. CONCLUSIONS: Low PTEN expression in patients treated with cetuximab plus chemotherapy emerged as a prognostic biomarker and should be evaluated for its predictive role for cetuximab efficacy.

The Impact of Addition of Consolidation Chemotherapy to Standard Cisplatin-Based Chemoradiotherapy in Uterine Cervical Cancer: Matter of Distant Relapse.

BACKGROUND: Treatment of advanced uterine cervical cancer has advanced little in the last 15 years. Although two phase III trials showed survival benefit with the addition of consolidation chemotherapy (CT) after cisplatin-based chemoradiotherapy (RTCT), it is not considered standard of care. We aimed to evaluate the benefit of consolidation CT compared to no additional treatment in patients treated with RTCT. METHODS: This is a retrospective study including 186 patients with FIGO stage IB2, IIA2, or IIB to IVB (paraaortic lymph nodes only) uterine cervical cancer who were treated with standard RTCT alone or RTCT followed by consolidation CT. Overall survival (OS), progression free survival (PFS), and the risk of distant and local relapses were compared between the two treatment groups. RESULTS: At 3 years OS was 91% versus 82.3% (p=0.027), PFS 84.3% versus 54.4% (p=0.047), and distant metastasis free survival (DMFS) 80.4% versus 62.5% (p=0.027) in favor of the consolidation CT group. Multivariate analysis confirmed the benefit of consolidation CT. There was no difference in locoregional free survival (LRFS). Positive lymph node was related to a higher risk of distant relapse. In the lymph node positive subgroup consolidation CT resulted in longer OS (p=0.050), PFS (p=0.014), and DMFS (p=0.022); in the lymph node negative subgroup there was no benefit from consolidation CT. CONCLUSIONS: Use of consolidation CT resulted in longer OS and PFS, mostly due to control of distant relapses. Patients at higher risk of distant relapse showed the greatest benefit. This data generates a hypothesis that could help to better select patients to consolidation CT.

The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma.

There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response.